title: SDF-1-CXCR4 differentially regulates autoimmune diabetogenic T cell adhesion through ROBO1-SLIT2 interactions in mice.
abstract: OBJECTIVE
  We had previously reported that stromal cell-derived factor 1 (SDF-1) mediates chemorepulsion of diabetogenic T cell adhesion to islet microvascular endothelium through unknown mechanisms in NOD mice. Here we report that SDF-1-mediated chemorepulsion occurs through slit homologue (SLIT)2-roundabout, axon guidance receptor, homologue 1 (Drosophila) (ROBO1) interactions.
  
  
  METHODS
  C-X-C receptor (CXCR)4 and ROBO1 protein expression was measured in mouse and human T cells. Parallel plate flow chamber adhesion and detachment studies were performed to examine the molecular importance of ROBO1 and SLIT2 for SDF-1-mediated T cell chemorepulsion. Diabetogenic splenocyte transfer was performed in NOD/LtSz Rag1(-/-) mice to examine the effect of the SDF-1 mimetic CTCE-0214 on adoptive transfer of diabetes.
  
  
  RESULTS
  CXCR4 and ROBO1 protein expression was elevated in diabetic NOD/ShiLtJ T cells over time and coincided with the onset of hyperglycaemia. CXCR4 and ROBO1 expression was also increased in human type 1 diabetic T cells, with ROBO1 expression maximal at less than 1 year post diagnosis. Cell detachment studies revealed that immunoneutralisation of ROBO1 prevented SDF-1-mediated chemorepulsion of NOD T cell firm adhesion to TNFα-stimulated islet endothelial cells. SDF-1 increased NOD T cell adhesion to recombinant adhesion molecules, a phenomenon that was reversed by recombinant SLIT2. Finally, we found that an SDF-1 peptide mimetic prevented NOD T cell adhesion in vitro and significantly delayed adoptive transfer of autoimmune diabetes in vivo.
  
  
  CONCLUSIONS
  These data reveal a novel molecular pathway, which regulates diabetogenic T cell recruitment and may be useful in modulating autoimmune diabetes.
authors.affiliation: Department of Pathology, LSU Health-Shreveport, 1501 Kings Highway, Shreveport, LA 71130, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Glawe
authors.forename: Eleni M
authors.initials: EM
authors.lastname: Mijalis
authors.forename: William C
authors.initials: WC
authors.lastname: Davis
authors.forename: Shayne C
authors.initials: SC
authors.lastname: Barlow
authors.forename: Neslihan
authors.initials: N
authors.lastname: Gungor
authors.forename: Robert
authors.initials: R
authors.lastname: McVie
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Kevil
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002448:Cell Adhesion / Q000502:physiology; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D054387:Receptors, CXCR / Q000235:genetics / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein
chemical_list: D054377:Chemokine CXCL12; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D054387:Receptors, CXCR; D019718:Receptors, CXCR4; D011971:Receptors, Immunologic; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein; C501897:Cmkor1 protein, mouse